title: Antibody ligation of murine Ly-6G induces neutropenia, blood flow cessation, and death via complement-dependent and independent mechanisms.
abstract: Ly-6G is a member of the Ly-6 family of GPI-linked proteins, which is expressed on murine neutrophils. Antibodies against Ly-6G cause neutropenia, and fatal reactions also develop if mice are primed with TNF-alpha prior to antibody treatment. We have investigated the mechanisms behind these responses to Ly-6G ligation in the belief that similar mechanisms may be involved in neutropenia and respiratory disorders associated with alloantibody ligation of the related Ly-6 family member, NB1, in humans. Neutrophil adhesion, microvascular obstruction, breathing difficulties, and death initiated by anti-Ly-6G antibodies in TNF-alpha-primed mice were shown to be highly complement-dependent, partly mediated by CD11b, CD18, and FcgammaR and associated with clustering of Ly-6G. Neutrophil depletion, on the other hand, was only partly complement-dependent and was not altered by blockade of CD11b, CD18, or FcgammaR. Unlike other neutrophil-activating agents, Ly-6G ligation did not induce neutropenia via sequestration in the lungs. Cross-linking Ly-6G mimicked the responses seen with whole antibody in vivo and also activated murine neutrophils in vitro. Although this suggests that the responses are, in part, mediated by nonspecific properties of antibody ligation, neutrophil depletion requires an additional mechanism possibly specific to the natural function of Ly-6G.
authors.affiliation: Cardiovascular Research Unit, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, S10 2JF, UK.
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Abbitt
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Cotter
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Ridger
authors.forename: David C
authors.initials: DC
authors.lastname: Crossman
authors.forename: Paul G
authors.initials: PG
authors.lastname: Hellewell
authors.forename: Keith E
authors.initials: KE
authors.lastname: Norman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000950:Antigens, Ly / Q000276:immunology*; D039481:CD11b Antigen / Q000276:immunology; D018821:CD18 Antigens / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology*; D003432:Cross-Linking Reagents; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000276:immunology; D009503:Neutropenia / Q000276:immunology* / Q000401:mortality / Q000503:physiopathology; D009504:Neutrophils / Q000276:immunology*; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D012119:Respiration; D012131:Respiratory Insufficiency / Q000276:immunology* / Q000401:mortality / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000950:Antigens, Ly; D039481:CD11b Antigen; D018821:CD18 Antigens; D003432:Cross-Linking Reagents; C494192:Ly-6C antigen, mouse; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha; D003165:Complement System Proteins